The human T lymphotropic virus type I (HTLV-I) is associated with a chronic-progressive myelopathy known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease clinically similar to the chronic-progressive form of multiple sclerosis (MS). An understanding of the pathogenesis of a neurologic disease such as HAM/TSP will aid in defining similar mechanisms in MS, a disease of unknown etiology. Five major areas of research are being targeted: (1) the host immune response in the HAM/TSP disease process and the role of CD8+, CTL, and cytokines; (2) the in situ detection of retroviral sequences in the central nervous system and lymphoid organs of HAM/TSP patients; (3) the construction of HTLV-I transgenes that express HTLV-I gene products in a tissue-specific manner; (4) the molecular characterization of potentially novel human retroviruses isolated from patients with other chronic-progressive neurologic diseases, including MS; and (5) immunotherapeutic strategies for the treatment of HAM/TSP. The major findings of these studies are: (1) the demonstration of CD8+, CTL directly isolated from PBL or CSF of HAM/TSP patients that use a limited set of T- cell receptors; (2) the establishment of an ELISPOT assay to quantify the number of cytokine ( gamma-IFN, IL-2, IL-4) producing cells in HAM/TSP patients PBL and has shown a high frequency in these patients; (3) HTLV-I tax mRNA signals were detected in spinal cord lesions of HAM/TSP patients and have been colocalized to astrocytes; (4) the technique of in situ-PCR has amplified HTLV-I tax DNA from the CNS of HAM/TSP patients and has also demonstrated a large reservoir of HTLV-I-infected cells in bone marrow; (5) an HTLV-I tax construct has been developed under control of an astrocyte-specific promoter in which HTLV-I tax RNA is produced in cells of astroglial origin. Transgenic mice are being developed; (6) strong seroreactivity to HTLV- related antigens has been demonstrated from a number of patients with chronic-progressive myelopathies, and attempts to molecularly identify this potentially novel retrovirus are being pursued; (7) HTLV-II is continuing to be associated with chronic myelopathies; and (8) a phase I/II trial of humanized anti-IL2 receptor antibody in the treatment of HAM/TSP has begun in which immunologic affects have been demonstrated. These results continue to define the role of human retroviruses that are associated with chronic- progressive neurologic disease.